The optimal treatment for chronic hepatitis B remains controversial. Published guidelines from several sources suggest initiating antiviral therapy, in general, when serum ALT activity is abnormal and when significant liver disease is present. These recommendations have largely been developed by balancing the likelihood of response as measured in short-term studies against the likelihood of developing viral resistance during extended therapy. However, these guidelines have never been prospectively evaluated to determine whether they truly represent the best strategy for selecting candidates for treatment. Furthermore, recent epidemiologic data indicate that the presence of high level HBV viremia itself is an important risk factor for subsequent cirrhosis and hepatocellular carcinoma, suggesting that rigid adherence to treatment guidelines may disadvantage many patients for whom long-term viral suppression may be beneficial. The current availability of multiple potent antiviral agents with good safety profiles and a seemingly low risk of resistance provide an opportunity to optimize strategies to treat chronic hepatitis B. This proposal will focus on the design of 1) a research database and specimen repository and 2) a collaborative multicenter trial to corroborate current treatment guidelines while comparing the long-term efficacy and safety of monotherapy vs. combination therapy. The study design will further refine the identification and management of hepatitis B viral resistance during extended therapy, and provide important information regarding the long-term outcomes associated with treatment. Our proposal to participate as a Clinical Center for this cooperative study will emphasize the experience, unique attributes, and patient population of the Liver Program at the University of North Carolina at Chapel Hill, in collaboration with Duke University, and Carolinas Medical Center, which will ensure successful completion of these studies as a member of the Hepatitis B Clinical Research network.